Viral Load "Blips" Linked to Kidney Dysfunction, Role of Tenofovir Remains Unclear

By Liz Highleyman

Loss of kidney function is a concern for people with HIV, especially individuals of African descent. Several factors have been implicated in renal dysfunction, including HIV-associated immunodeficiency, viral replication, antiretroviral drug toxicity, and possibly inflammation and other poorly understood processes that result in higher rates of serious non-AIDS comorbidities.

GFR Changes in Treated and Untreated HIV Patients

To shed further light on these factors, Andy Choi and colleagues from the University of California at San Francisco compared rates of kidney function decline in 4 groups of HIV patients as defined by degree of viral replication in the presence or absence of antiretroviral therapy (ART):

Untreated controllers (HIV RNA < 1000 copies/mL);

Untreated non-controllers (HIV RNA > 1000 copies/mL);

ART-treated controllers;

ART-treated non-controllers.

As Choi described in an oral presentation at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal, the investigators estimated rates of change in kidney function among 615 participants enrolled in the SCOPE cohort.

Most participants (87%) were men, the mean age was 45 years, and they had relatively well-preserved immune function, with a mean CD4 count of about 430 cells/mm3. Participants were not excluded on the basis of existing kidney disease, nor were they stratified based on race (about half were white, one-third black).

Kidney function was estimated using the MDRD (Modification of Diet in Renal Disease) equation, which calculates glomerular filtration rate (GFR) based on age, sex, race, and serum creatinine.

Results

In an unadjusted analysis, over a median 2.7 years of follow-up, the GFR change was -2.6 mL/min/1.73m2 per year in HIV positive people versus -0.4 mL/min/1.73m2 per year in the HIV negative population.

Among patients first initiating ART, the rate of GFR decline slowed after starting therapy (+2.8 mL/min/1.73m2 per year).

In a multivariate analysis adjusting for potential confounding factors, the rate of GFR decline was:

Lowest among untreated controllers;

Highest among untreated non-controllers;

Intermediate in the 2 ART-treated groups.

Relative to untreated controllers, rates of GFR decline in the other 3 groups were as follows:

Untreated non-controllers: -5.8 mL/min/1.73m2/year;

ART-treated controllers: -5.2 mL/min/1.73m2/year;

ART-treated non-controllers: -5.5 mL/min/1.73m2/year.

Despite suppressed viral load, ART-treated controllers experienced continued GFR loss (-1.6 mL/min/1.73m2/year).

In this group, transient increases in HIV viral load ("blips") were strongly associated with GFR decline.

Each 1 log increase in HIV RNA was associated with GFR loss of -6.9 mL/min/1.73m2/year.

Changes in CD4 cell count, however, were not linked to GFR changes.

Older age, female sex, elevated blood lipids, and diabetes were also significant predictors of kidney function decline.

Based on these findings, the researchers concluded, "Although ART appears to help curb kidney function decline among those with uncontrolled viremia, patients who have achieved durable viral suppression continue to lose kidney function above age-expected norms."

"Overall kidney function loss is more closely associated with viremia, whereas the level of immunodeficiency (as defined by CD4 count) does not appear to be a major prognostic factor in either untreated or treated disease," they added.

Discussing the findings, Choi said that ART may reverse some kidney function decline, but it was "not completely benign," since treated HIV positive individuals still had greater decline than HIV negative people.

He added that his group plans to look more closely at inflammation, which may help explain the detrimental effect on kidney function of ongoing HIV replication.

Responding to a question about the significance of low viral load, Choi stated that "perfect controllers" with less than 50 copies/mL had a reduced rate of GFR loss compared to people with 50-1000 copies/mL.

He also noted that while the study was underpowered to analyze differences between specific antiretroviral drugs, there was no evident effect of any particular drugs, including tenofovir (Viread, also in the Truvada and Atripla combination pills) and indinavir (Crixivan).

Factors Associated with Kidney Function Decline

In the same session, Sonia Rodriguez-Novoa from Hospital Carlos III in Madrid, Spain, reported findings from a study that looked at genetic variations associated with tenofovir-related kidney tubule damage.

In some studies, tenofovir -- which is excreted by the kidneys -- has been associated with decreased kidney function, especially in people with pre-existing risk factors, although clinical kidney dysfunction was not observed in clinical trials that supported the drug's approval.

The mechanism underlying the effect of tenofovir on the kidney is not fully understood, but alterations in tubular transporter proteins may play a role. In this analysis, the investigators evaluated a range of single nucleotide polymorphisms (SNPs), or genetic changes at specific positions, on genes thought to code for relevant drug transporter proteins.

The study included 154 HIV patients taking tenofovir-containing ART regimens, 49 participants on ART without tenofovir, and 81 treatment-naive HIV patients. A majority were Caucasian. A subset of 115 tenofovir recipients were included in the pharmacogenetic analysis, 19 with and 96 without kidney dysfunction.

Altered kidney tubular function was defined as having at least 2 of the following: non-diabetic glucosuria (glucose in the urine), urine phosphate wasting, hyperaminoaciduria (elevated levels of amino acids in the urine), beta2-microglobulinuria, or increased fractional excretion of uric acid.

The researchers found that 22% of tenofovir recipients, 6% of patients on non-tenofovir ART, and 12% of treatment-naive individuals had kidney tubular dysfunction. Abnormal function was more common in people with the ABCC2-24 GG genotype than in those with genotypes GT or TT (24% vs 6%). Specific SNPs on the ABCC2 (aka MRP2), ABCC4 (MRP4), and SLC22A11 (OAT4) genes were linked to particular manifestations of kidney dysfunction.

In a multivariate analysis the only factors independently associated with altered kidney tubular function were older age, lower weight, and most strongly GG genotype (odds ratio 5.7).

"Genetic analysis of ABCC2-24 could help to identify patients at greater risk for renal tubulopathy," the investigators concluded. "Since [tenofovir] has been shown not to serve as a substrate for ABCC2, the precise mechanism of this association requires elucidation. Close monitoring of renal function is warranted in this subset of patients."

3/10/09

References

A Choi, M Shlipak, P Hunt, and others. HIV-infected Persons Continue to Lose Kidney Function despite Successful ART. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 38.

S Rodriguez Novoa, P Labarga, V Soriano, and others. Predictors of Kidney Tubulopathy in HIV Patients Treated with Tenofovir: A Pharmacogenetic Study. CROI 2009. Montreal, Canada. February 8-11, 2009. Abstract 37.